DARS-AS1: A Vital Oncogenic LncRNA Regulator with Potential for Cancer Prognosis and Therapy

DARS-AS1, short for Aspartyl-tRNA synthetase antisense RNA 1, has emerged as a pivotal player in cancers. Upregulation of this lncRNA is a recurrent phenomenon observed across various cancer types, where it predominantly assumes oncogenic roles, exerting influence on multiple facets of tumor cell biology. This aberrant expression of DARS-AS1 has triggered extensive research investigations, aiming to unravel its roles and clinical values in cancer. In this review, we elucidate the significant correlation between dysregulated DARS-AS1 expression and adverse survival prognoses in cancer patients, drawing from existing literature and pan-cancer analyses from The Cancer Genome Atlas (TCGA). Additionally, we provide comprehensive insights into the diverse functions of DARS-AS1 in various cancers. Our review encompasses the elucidation of the molecular mechanisms, ceRNA networks, functional mediators, and signaling pathways, as well as its involvement in therapy resistance, coupled with the latest advancements in DARS-AS1-related cancer research. These recent updates enrich our comprehensive comprehension of the pivotal role played by DARS-AS1 in cancer, thereby paving the way for future applications of DARS-AS1-targeted strategies in tumor prognosis evaluation and therapeutic interventions. This review furnishes valuable insights to advance the ongoing efforts in combating cancer effectively.

LncRNAs are classified into several categories, such as antisense, sense, intronic, and intergenic, each possessing unique characteristics [27].Focusing on antisense lncRNAs, these transcripts are uniquely synthesized from the opposite DNA strand of genes that may encode proteins or serve non-coding functions, leading to their critical role in the onset and development of tumors, which has recently garnered attention [28][29][30][31].At the molecular level, they execute regulatory functions through a series of mechanisms, encompassing epigenetic modification, transcriptional control, post-transcriptional regulation, and impacts on translation [16,28,32].Additionally, due to their nucleotide sequence complementarity,

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International Publisher antisense lncRNAs possess a distinctive regulatory capability, specifically targeting and interacting with their corresponding sense genes [28], further highlighting the complexity of their involvement in cellular and pathological processes, particularly within the realm of cancer.

Expression of DARS-AS1 in tumor tissues
DARS-AS1, an emerging tumor marker, exhibits significant upregulation in a diverse array of cancer types based on research involving in-house tissue specimens and analyses of TCGA data (Table 1).These cancer types span various bodily systems, including the neurological system (such as brain lower-grade glioma and glioblastoma), the respiratory system (including non-small cell lung cancer, and mesothelioma), the digestive system (comprising gastric cancer, liver cancer, and colorectal cancer), the urinary system (featuring renal cell carcinoma), the female reproductive system (encompassing cervical and ovarian cancers), and the hematological system (including myeloma and acute myeloid leukemia).Additionally, DARS-AS1 demonstrates upregulation in other tumor types, such as bladder cancer, prostate adenocarcinoma, uveal melanoma, breast cancer, and osteosarcoma.These findings suggest that DARS-AS1 may hold significance as a potential biomarker or therapeutic target across a wide spectrum of cancers, warranting further investigation into its specific roles and clinical applications.

LncRNA DARS-AS1 is associated with tumor-related clinical features
Several investigations have explored the relationship between DARS-AS1 expression and clinicopathological characteristics across a spectrum of five tumor types (Table 1).In gastric cancer [51], DARS-AS1 exhibits a significant positive correlation with T category, N category, TNM stage.In hepatocellular carcinoma [35], overexpression DARS-AS1 indicates larger tumor size and advanced TNM stage.In clear cell renal cell carcinoma [36] and triple-negative breast cancer [40], high expression of DARS-AS1 is indicative of higher clinical-stage.In acute myeloid leukemia [34], patients with high DARS-AS1 expression exhibit a significantly higher leukocyte count in peripheral blood, while their hemoglobin levels and platelet counts are notably lower compared to those with low DARS-AS1 expression.

LncRNA DARS-AS1 is a valuable prognostic marker
LncRNA DARS-AS1 serves as a valuable prognostic indicator.The abnormal expression of DARS-AS1 has been closely associated with overall survival (OS) in cancer patients.As summarized in Table 1, drawing from both the in-house survival data and TCGA analyses conducted in these studies for OS, high levels of DARS-AS1 expression are predictive of poorer OS in a range of cancer types, including gastric cancer, hepatocellular carcinoma, lung adenocarcinoma, triple-negative breast cancer, cervical cancer, acute myeloid leukemia, UVM, KICH, KIRP, MESO, GBM, and LGG.
In addition to the effect on OS, we also performed a comprehensive assessment of the prognostic relevance of DARS-AS1 in a pan-cancer analysis using TCGA, considering disease-specific survival (DSS), disease-free interval (DFI) and progression-free interval (PFI).

Functions of DARS-AS1 in human tumors
Extensive research has been conducted on the role of DARS-AS1 in twelve different types of tumors, utilizing in vivo and/or in vitro experiments (Table 2).DARS-AS1 expression has been consistently observed to be up-regulated in numerous tumor cell lines.The subcellular localization of this lncRNA was reported within the cytoplasm in six different types of tumor cells, including clear cell renal cell carcinoma, cervical cancer, acute myeloid leukemia, colorectal cancer, and glioblastoma cells.DARS-AS1 plays a pivotal oncogenic role in tumor development, impacting a series of biological processes (Figure 3).It promotes epithelial-mesenchymal transition (EMT), augments cell proliferation, enhances cell viability, facilitates migration and invasion, induces autophagy, contributes to therapy resistance, facilitates tumor growth, and metastasis.Conversely, DARS-AS1 inhibits apoptosis and hinders cell cycle arrest in tumor cells.These findings emphasize the profound importance of DARS-AS1 as a critical oncogenic regulator influencing various aspects of tumor progression.
BBOX1-AS1 exerts its regulatory influence across various types of tumors by competitively binding to a diverse range of miRNAs.Furthermore, it contributes to the progression of distinct tumor types by influencing common miRNAs.Intriguingly, in the context of a single tumor, BBOX1-AS1 can engage with multiple miRNAs to impact tumor development.For instance, in cervical cancer [33,49], BBOX1-AS1 engages in two distinct ceRNA mechanisms, thereby promoting both the proliferation and apoptosis of cervical cancer cells.These mechanisms involve the targeting of miR-628-5p/JAG1 [33] and miR-188-5p/HMGB1 [49].

LncRNA DARS-AS1 as Functional Modules in Tumors
DARS-AS1 is a versatile regulator of gene expression, operating through ceRNA networks, as described above.However, it also exerts its influence in gene regulation by functioning as a modular scaffold, protein decoy, and molecular mediator impacting downstream targets.
When functioning as a molecular mediator, in triple-negative breast cancer [41], DARS-AS1 overexpression significantly upregulated the levels of TGF-β, p-Smad3, ATG5, and the conversion from LC3-I to LC3-II.Conversely, silencing DARS-AS1 reversed these effects.Silencing DARS-AS1 enhanced the sensitivity of triple-negative breast cancer (TNBC) cells to doxorubicin by suppressing autophagy induced by the TGF-β/Smad3 signaling pathway, thereby strengthening the synergistic antitumor effects.In cervical cancer [37], ATP1B2 was identified as a target mRNA of DARS-AS1, and it showed a negative correlation with DARS-AS1 expression.DARS-AS1/ATP1B2 partially regulated malignant behaviors through the cGMP-PKG signaling pathway.
When serving as a modular scaffold, in cervical cancer [43], DARS-AS1 enhanced DARS mRNA stability and translation by recruiting METTL3 and METTL14.Moreover, DARS-AS1 positively regulated IGF2BP3 expression by stabilizing IGF2BP3 mRNA.In glioblastoma [47], DARS1-AS1 interacted with YBX1 to promote the binding and stability of target mRNA.This established a mixed transcriptional/posttranscriptional feed-forward loop, enhancing the expression of key regulators of the G1-S transition, including E2F1 and CCND1.DARS1-AS1/YBX1 also increased the stability of FOXM1 mRNA, a master transcription factor regulating GSC self-renewal and DSB repair.
When acting as a protein decoy, in colorectal cancer [46], DARS-AS1 directly bound to PACT.This interaction inhibited the association between PACT and PKR, preventing the phosphorylation of the PKR downstream substrate eIF2α, ultimately inhibiting apoptotic cell death.In breast cancer and HCC [46], DARS-AS1 promoted cancer cell proliferation and inhibited apoptosis by inhibiting the function of PACT.In myeloma [44], DARS-AS1 exerts its function by binding RNA-binding motif protein 39 (RBM39), which impedes the interaction between RBM39 and its E3 ubiquitin ligase RNF147 and prevents RBM39 from degradation.
The intricate interplay of ceRNA networks and DARS-AS1's interactions with both mRNA and protein constituents endow it with a multifaceted role as a gene expression regulator.The perturbation of DARS-AS1 in cancer underscores its significance as a plausible therapeutic target, underscoring the urgency for in-depth exploration of its exact functionalities and molecular associations.

Signaling pathways influenced by lncRNA DARS-AS1
Accumulating scientific findings support the pivotal role of lncRNAs in orchestrating various signaling pathways [63][64][65][66][67], offering fresh perspectives for the development of targeted therapies.Presently, DARS-AS1 has been unequivocally established as an important participant in the regulation of multiple cancer-related signaling pathways, as outlined in Figure 5.These pathways encompass the FAK/ERK, PI3K/AKT, NF-κB/ STAT3, TGF-β/Smad3, Notch, cGMP-PKG, mTOR, and PACT-PKR pathways.The involvement of DARS-AS1 in these intricate signaling networks implies its broader influence on the behavior of cancer cells and their responses to therapy.
In hepatocellular carcinoma [35], DARS-AS1 up-regulates CKAP2 by binding to miR-3200-5p, thereby activating the FAK-ERK pathway and promoting HCC proliferation and metastasis, and DARS-AS1 is also reported to promote HCC cell proliferation and inhibits apoptosis through inhibiting the function of PACT [46].In lung adenocarcinoma [42], it was found that DARS-AS1 significantly enhances the malignant properties of LUAD cells.This effect was achieved through the activation of the PI3K/AKT pathway, triggering the EMT process, and the up-regulation of Cyclin D1 and Bcl-2 proteins, both recognized contributors to cell growth and survival.In breast cancer, DARS-AS1 promote the TNBC tumorigenesis by activation of the NF-κB/STAT3 signaling pathway [40], and increased the resistance of TNBC cells to doxorubicin by promote TGF-β/Smad3 signaling pathway-induced autophagy [41].In addition, DARS-AS1 inhibits breast cancer cell proliferation, which is, at least partially, through repressing PACT-mediated PKR activation [46].In cervical cancer, DARS-AS1 exhibits pro-tumorigenic effects by activating the Notch pathway [33], and cGMP-PKG pathway [37], exacerbating the tumorigenesis of cervical cancer.In myeloma, Tong et al. [44] revealed that hypoxia-induced lncRNA DARS-AS1 upregulates RBM39 protein expression via the ubiquitinproteasome pathway, and further promotes mTOR signaling pathway to promote myeloma malignancy.In colorectal cancer [46], lncRNA DARS-AS1 is directly involved in the inhibition of the PACT-PKR pathway and promotes the proliferation and inhibit cancer cell apoptosis, and promote tumor growth in vivo.
Doxorubicin is the primary chemotherapy drug utilized to enhance the survival of triple-negative breast cancer patients [78][79][80].However, it often leads to strong drug resistance during its usage.Liu et al. [41] reported that silencing DARS-AS1 decreases doxorubicin resistance by suppressing autophagy via inhibition of the TGF-β/Smad3 signaling pathway, and combination of DARS-AS1 siRNA and DOX significantly inhibited tumorigenesis and growth of TNBC cells, which indicated that combination of DARS-AS1 siRNA and doxorubicin can be used as new therapeutic agents for TNBC.
In the context of myeloma [44], lncRNA DARS-AS1 is directly upregulated by hypoxia inducible factor-1.And overexpression of DARS-AS1 resulted in a decreased responsiveness of myeloma cells to bortezomib.Additionally, Zheng et al. [47] investigated the impact of BBOX1-AS1 on glioblastoma tumorigenesis/radioresistance by multiomics analyses, and revealed that DARS1-AS1 depletion impaired the homologous recombination (HR)mediated double-strand break (DSB) repair and enhanced the radiosensitivity of glioblastoma cells.Overall, exploring the molecular mechanisms of the DARS1-AS1-associated regulatory axis in drug and radiotherapy resistance could provide valuable insights for the development of targeted therapies and improved clinical outcomes for cancer patients.

Future perspectives
In recent years, DARS1-AS1, as an emerging oncogenic lncRNA, has been consistently found to be upregulated in various cancer types.Notably, DARS1-AS1 demonstrates significant clinical relevance in prognostic predictions.Studies have revealed that DARS1-AS1 plays a regulatory role in tumor development by influencing key molecules and genes involved in critical tumor-related biological processes, as shown in Figure 6.These findings highlight the potential therapeutic implications of targeting DARS1-AS1 in cancer treatment.
In terms of mechanisms, DARS-AS1 plays a crucial role as a multifaceted functional module, encompassing activities such as ceRNA, modular scaffold, protein decoy, and molecular mediator functions.It intricately influences gene expression and modulates signaling pathways, thereby regulating biological processes associated with tumorigenesis and progression.As a ceRNA, lncRNA DARS-AS1 binds to microRNA, leading to the upregulation of target genes such as NAT10, DARS, CDK1, JAG1, and HMGB1, and thus exhibits a broader regulatory effect on the development of different tumors.Notably, lncRNA DARS-AS1 is intricately involved in many signaling pathways, such as FAK/ERK, PI3K/AKT, NF-κB/STAT3, TGF-β/ Smad3, Notch, cGMP-PKG, mTOR.Among these pathways, lncRNA DARS-AS1 plays an activating role, affecting key processes in cancer initiation and progression.By engaging with these signaling pathways, lncRNA DARS-AS1 plays a central role in shaping the dynamics of cancer cells, promoting their survival and enhancing their invasive and metastatic potential.And lncRNA DARS-AS1 inactivates PACT-PKR pathway, promotes proliferation and inhibits apoptotic cell death in multiple cancer cells.Remarkably, diminished levels of DARS1-AS1 expression demonstrated heightened susceptibility to both drug and radiation therapies, suggesting a potential avenue for augmenting the efficacy of current cancer treatment modalities.Overall, the intricate array of functions attributed to DARS1-AS1, encompassing its role as a ceRNA, functional modules, and its influence on pivotal signaling pathways, positions it as a promising therapeutic target for pioneering cancer interventions designed to combat metastasis and enhance treatment responses.
Despite the progress made, our understanding of DARS1-AS1 remains incomplete.Further studies are needed to assess DARS1-AS1 expression in hematopoietic cancers and to determine its impact on tumor progression and prognosis in larger study populations of different tumor types.In addition, no studies have explored the diagnostic potential of DARS1-AS1.It is imperative to evaluate the diagnostic value of DARS1-AS1 for cancer.In particular, the clinical value of detection of DARS1-AS1 in liquid tissue in the early diagnosis of tumors deserves further study.Furthermore, it is essential to acquire a more profound understanding of the specific regulatory mechanisms of DARS1-AS1 in various tumor types.DARS1-AS1 might be intricately connected to additional signaling pathways and could possess a broader ceRNA network.In vitro and in vivo studies are needed to elucidate the mechanisms through which DARS1-AS1 contributes to therapy resistance across diverse tumor types.

Conclusion
In a nutshell, DARS-AS1 is an oncogenic lncRNA consistently overexpressed in various cancers, strongly linked to poor patient outcomes.Research in lab and live settings reveals its cancer-promoting role in tumor processes through ceRNA networks and signaling pathways.DARS-AS1 holds promise as a cancer biomarker and therapeutic target, but more research and clinical validation are needed to fully understand its mechanisms and potential applications in cancer management.

Figure 6 .
Figure 6.Summary of the molecular mechanisms of lncRNA DARS-AS1 as a central regulator of cellular processes in cancer.This figure provides an overview of how lncRNA DARS-AS1 serves as a central regulator of cellular processes in cancer.It influences gene expression through ceRNA networks and functions as a versatile entity.DARS-AS1 acts as a modular scaffold, protein decoy, and molecular mediator, thereby impacting downstream targets in gene regulation.

Table 1 .
Correlations between the expression levels of lncRNA DARS-AS1 in tumor tissues, clinical characteristics, and prognostic outcomes.

Table 2 .
Functions and regulatory mechanisms of lncRNA DARS-AS1 in different cancers.